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Study Design Phase I/II Study of Bendamustine in Combination with Ofatumumab, Carboplatin and Etoposide for Refractory or Relapsed Aggressive B-cell Lymphomas. AUTHORS Principal Investigator Joanne Filicko-O’Hara, MD Co-Investigators S. Onder Alpdogan, MD Matthew Carabasi, MD Jerald Gong, MD Margaret Kasner, MD Neal Flomenberg, MD Ubaldo Martinez, MD John L.Wagner, MD Dolores Grosso, DNP, CRNP Avnish Bhatia, MD Andrew Chapman, DO Michael Ramirez, MD Lewis Rose, MD Atrayee Basu-Mallick, MD Allison Zibelli, MD Christina Brus, MD Sameh Gaballa, MD Pierluigi Porcu, MD Neil Palmisiano, MD Lindsay Wilde, MD Biostatistician Inna Chervoneva, PhD Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation Department of Medical Oncology Kimmel Cancer Center Thomas Jefferson University 834 Chestnut Street, Suite # 320, Philadelphia, Pa 19107 Phone (215) 503-5894 Original Date: 7.19.11 (Version 1.0) Updated Protocol 1.12.12 (Version 1.2) Versions 7.31.12 (Version 1.3) 10.4.11 (Version 1.1) 1 Protocol Version 6.3 1.7.13 (Version 2.0) 4.2.13 (Version 2.1) 6.5.13 (Version 2.2) 3.12.14 (Version 3.0) 12.31.14 (Version 3.1) 2.4.15 (Version 3.2) 8.12.15 (Version 4.0) 9.10.15 (Version 5.0) 11.13.15 (Version 5.1) 02.11.16 (Version 5.2) 05.27.16 (Version 6.0) 03.10.17 (Version 6.1) 11.16.17 (Version 6.2) 09.17.18 (Version 6.3) 2 Protocol Version 6.3 INDEX STUDY SUMMARY 1 INTRODUCTION ……………………………………………………………………………………………………………..11 1.1 BACKGROUND …………………………………………………………………………………………………………………..11 1.2 INVESTIGATIONAL AGENT-OFATUMUMAB………………………………………………………………………………….13 1.2.1Preclinical Data………………………………………………………………………………………………………...13 1.2.2 Clinical Data…………………………………………………………………………………………………………….14 1.2.3 Adverse Events noted in Follicular Lymphoma Subjects………………………………………………14 1.2.4 Ofatumumab Combination Therapy…………………………………………………………………………..14 1.3 INVESTIGATIONAL AGENT-BENDAMUSTINE……………………………………………………………….15 1.4 OFATUMUMAB AND BENDAMUSTINE COMBINATION………………………………………………….16 1.5 STUDY RATIONALE …………………………………………………………………………………………………….17 1.6 RATIONALE FOR CORRELATIVE STUDIES…………………………………………………………………….17 1.6.1 Analysis of the surface expression og CD20 on malignant cells in relapsed aggressive B cell lymphoma…………………………………………………………………………………………………………………………17 1.6.2 Biologic profile of relapsed and refractory aggressive B cell lymphoma……………………18 1.6.3 Validation of oligo nucleotide based microarray platform for NHL risk stratification…..19 2 STUDY OBJECTIVES………………………………………………………………………………………………………….19 2.1 PRIMARY OBJECTIVE FOR PHASE I PART OF STUDY………………………………………………………19 2.2 SECONDARY OBJECTIVE FOR PHASE I……………………………………………………………………………20 2.3 PRIMARY OBJECTIVE FOR PHASE II STUDY……………………………………………………………………20 2.4 SECONDARY OBJECTIVES FOR PHASE II STUDY……………………………………………………………..20 3 STUDY DESIGN………………………………………………………………………………………………………………….20 3.1 GENERAL DESIGN PHASE I……………………………………………………………………………………………..20 3.2 GENERAL DESIGN PHASE II……………………………………………………………………………………………22 3.3 PRIMARY STUDY ENDOPINT PHASE I……………………………………………………………………………..22 3.4 SECONDARY STUDY ENDPOINTS PHASE 1………………………………………………………………………22 3.5 PRIMARY STUDY ENDPOINTS PHASE II…………………………………………………………………………22 3.6 SECONDARY STUDY ENDPOINTS PHASE II………………………………………………………………………22 3.7 PRIMARY SAFETY ENDPOINTS ………………………………………………………………………………………23 4 SUBJECT SELECTION AND WITHDRAWAL…………………………………………………………………………23 4.1 INCLUSION CRITERIA………………………………………………………………………………………………………..23 4.2 EXCLUSION CRITERIA……………………………………………………………………………………………………….24 4.3 SUBJECT RECRUITMENT AND SCREENING………………………………………………………………………………25 4.4 EARLY WITHDRAWAL OF SUBJECTS……………………………………………………………………………………...26 4.4.1 When and How to Withdraw Subjects…………………………………………………………………………26 4.4.2 Data Collection and Follow-up for Withdrawn Subjects……………………………………………….26 5 STUDY DRUGS……………………………………………………………………………………………………………….........26 3 Protocol Version 6.3 5.1 OFATUMUMAB………………………………………………………………………………………………………………..26 5.2 BENDAMUSTINE……………………………………………………………………………………………………………...29 5.3 ETOPOSIDE……………………………………………………………………………………………………………………...31 5.4 CARBOPLATIN………………………………………………………………………………………………………………....33 5.5 TREATMENT REGIMEN…………………………………………………………………………………………………….34 5.5.1 Chemotherapy Regimen………………………………………………………………………………………………..34 5.5.2 Supportive Care……………………………………………………………………………………………………………34 5.5.2.1 Pre-medication……………………………………………………………………………………………………………..34 5.5.2.2 Ofatumumab infusion……………………………………………………………………………………………………35 5.5.2.3 Tumor Lysis prophylaxis………………………………………………………………………………………………..36 5.5.2.3 Tumor Lysis Prophylaxis……………………………………………………………………………………………………35 5.5.2.4 Growth factor support……………………………………………………………………………………………………35 5.5.2.5 Prophylaxis of Pneumocystis jirovecii………………………………………………………………………………35 5.5.2.6 Anti fungal Prophylaxis…………………………………………………………………………………………………..35 5.5.2.7 Anti viral prophylaxis……………………………………………………………………………………………………..35 5.5.2.8 Prophylaxis of CNS Disease..……………………………………………………………………………………………..35 5.6 Method for Assigning Subjects to Treatment Group……………………………..………………………….……35 5.7 PREPARATION AND ADMINISTRATION OF STUDY DRUG……………………………..………………………………..35 5.8 SUBJECT COMPLIANCE MONITORING……………………………..……………………………………………………….36 5.9 PRIOR AND CONCOMITANT THERAPY……………………………..……………………………………………………….36 5.10 RECEIVING, STORAGE, DISPENSING AND RETURN……………………………..……………………………………..…36 5.10.1 Receipt of Drug Supplies……………………………..……………………………………………………………….36 5.10.2 Storage……………………………..……………………………………………………………………………………….36 5.10.3 Dispensing of Study Drug……………………………………………………………………...……..………………36 5.10.4 Return or Destruction of Study Drug……………………………..………………………………………………36 6 STUDY PROCEDURES……………………………………………………………………………….37 6.1 SCHEMA……………………………………………………………………………………………………………………………37 6.2 STEM CELL MOBILIZATION AND STEM CELL TRANSPLANT……………………………………………….37 6.3 DOSE DELAYS AND DOSE REDUCTIONS……………………………………………………………………………..38 6.3.1 Cycle Delays ……………………………………………………………………………………………………………………..38 6.3.2 Dose Reduction of Bendamustine …………..…………………………………………………………………………...38 6.3.3 Dose Modifications of Carboplatin, Etoposide and Ofatumumab …………………………………………..38 6.4 DISEASE RESPONSE…………………………………………………………………………………………………………..39 6.5 CORRELATIVE STUDIES………………………………………………………………………………………………...….40 6.5.1 Flow Cytometry for CD20 Expression………………………………………………………………………………....40 6.5.2 Immunohistochemistry Studies…………………………………………………………………………………………..40 6.5.3 FISH Studies……………………………………………………………………………………………………………………...40 6.5.4 Analysis of EBER………………………………………………………………………………………………………………..40 6.5.5 Submission of Blood and Bone Marrow Samples……………………………………………………………………41 6.5.6 Freezing and Storage………………………………………………………………………………………………………….41 6.6 DURATION OF THERAPY ………………………………………………………………………………………………………...41 6.7 DURATION OF FOLLOW UP …………………………………………………………………………………………………….41 6.8 FOLLOW UP/MONITORING …………………………………………………………………………………………………….41 7 STATISTICAL PLAN……………………………………………………………………………………………………………….41 7.1 SAMPLE SIZE DETERMINATION…………………………………………………………………………………………………41 7.2 STATISTICAL METHODS…………………………………………………………………………………………………………..42 7.3 SUBJECT POPULATION(S) FOR ANALYSIS……………………………………………………………………………………..44 7.4 ANALYSIS OF MISSING DATA……………………………………………………………………………………………...44 8 SAFETY AND ADVERSE EVENTS…………………………………………………………………….44 8.1 DEFINITIONS…………………………………………………………………………………………………………………………44 8.2 RECORDING OF ADVERSE EVENTS…………………………………………………………………………………………….…47 4 Protocol Version 6.3 8.3 STOPPING RULES……………………………………………………………………………………………………………………47 8.4 LIVER CHEMISTRY STOPPING AND FOLLOW UP CRITERIA…………………………………………………..47 8.5 DATA AND SAFETY MONITORING PLAN………………………………………………………………………………………..50 8.5.1 Medical Monitoring and AE/SAE Reporting………………………………………………………………….……50 8.5.2 Data and Safety Monitoring Committee……………………………………………………………………….……51 9 DATA HANDLING AND RECORD KEEPING……………………………………………………………………….……………52 9.1 CONFIDENTIALITY…………………………………………………………………………………………………….……………..52 9.2 SOURCE DOCUMENTS………………………………………………………………………………………………….……………52 9.3 CASE REPORT FORMS………………………………………………………………………………………………………………52 9.4 RECORDS RETENTION………………………………………………………………………………………………………………53 10 STUDY MONITORING, AUDITING, AND INSPECTING………………………………….…………50 10.1 STUDY MONITORING PLAN…………………………………………………………………………………………………………50 10.2 AUDITING AND INSPECTING…………………………………………………………………………………………………………54 10.2.1 Independent External and Internal Audits…………..…………………………………………………………………54 11 ETHICAL CONSIDERATIONS…………………………………………………………………………..55 12 STUDY FINANCES………………………………………………………………………………………55 12.1 FUNDING SOURCE…………………………………………………………………………………………………………………..55 12.2 CONFLICT OF INTEREST……………………………………………………………………………………………………………55 13 PUBLICATION PLAN……………………………………………………………………………………55 14 REFERENCES…………………………………………………………………………………………….56 15 APPENDICES…………………………………………………………………………………………58 5 Protocol Version 6.3 List of Abbreviations ABC Activated B-cell–Type AE Adverse Event ANC Absolute Neutrophil Count ASCO American Society of clinical Oncology ASCT Autologous Stem Cell Transplant AUC Area Under the Curve BOCE Bendamustine, Ofatumumab, Carboplatin and Etoposide BUN Blood Urea Nitrogen CBC Complete Blood Count CCRRC Clinical Cancer Research Review Committee CDC Complement Dependent Cytotoxicity CD Cluster of Differentiation CHOP Cyclophosphamide, Doxorubicin, Vincristine and Prednisone CLL Chronic Lymphocytic Leukemia CMP Comprehensive Metabolic Panel CR Complete Response CRMO Clinical Research and Management Office DLBCL Diffuse Large B cell Lymphoma D5W 5% Dextrose in Water DLT Dose Limiting Toxicity DSMC Data
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